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Abstract Background Therapeutic lymphangiogenesis in an orthotopic lung transplant model has been shown to improve acute allograft rejection that is mediated at least in part through hyaluronan drainage. Lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expressed on the surface of lymphatic endothelial cells plays important roles in hyaluronan uptake. The impact of current immunosuppressive therapies on lung lymphatic endothelial cells is largely unknown. We tested the hypothesis that FK506, the most commonly used immunosuppressant after lung transplantation, induces lung lymphatic endothelial cell dysfunction. Methods Lung lymphatic endothelial cells were cultured in vitro and treated with FK506. Telomerase activity was measured using the TRAP assay. Protein expression of LYVE-1 and senescence markers p21 and β-galactosidase was assessed with western blotting. Matrigel tubulation assay were used to investigate the effects of FK506 on TNF-α-induced lymphangiogenesis. Dual luciferase reporter assay was used to confirm NFAT-dependent transcriptional regulation of LYVE-1. Flow cytometry was used to examine the effects of FK506 on LYVE-1 in precision-cut-lung-slices ex vivo and on hyaluronan uptake in vitro. Results In vitro, FK506 downregulated telomerase reverse transcriptase expression, resulting in decreased telomerase activity and subsequent induction of p21 expression and cell senescence. Treatment with FK506 decreased LYVE-1 mRNA and protein levels and resulted in decreased LEC HA uptake. Similar result showing reduction of LYVE-1 expression when treated with FK506 was observed ex vivo. We identified a putative NFAT binding site on the LYVE-1 promoter and cloned this region of the promoter in a luciferase-based reporter construct. We showed that this NFAT binding site regulates LYVE-1 transcription, and mutation of this binding site blunted FK506-dependent downregulation of LYVE-1 promoter-dependent transcription. Finally, FK506-treated lymphatic endothelial cells show a blunted response to TNF-α-mediated lymphangiogenesis. Conclusion FK506 alters lymphatic endothelial cell molecular characteristics and causes lymphatic endothelial cell dysfunction in vitro and ex vivo. These effects of FK506 on lymphatic endothelial cell may impair the ability of the transplanted lung to drain hyaluronan macromolecules in vivo. The implications of our findings on the long-term health of lung allografts merit more investigation.

Lung allograft rejection results in the accumulation of low–molecular weight hyaluronic acid (LMW-HA), which further propagates inflammation and tissue injury. We have previously shown that therapeutic lymphangiogenesis in a murine model of lung allograft rejection reduced tissue LMW-HA and was associated with improved transplant outcomes. Herein, we investigated the use of 4-Methylumbelliferone (4MU), a known inhibitor of HA synthesis, to alleviate acute allograft rejection in a murine model of lung transplantation. We found that treating mice with 4MU from days 20 to 30 after transplant was sufficient to significantly improve outcomes, characterized by a reduction in T cell–mediated lung inflammation and LMW-HA content and in improved pathology scores. In vitro, 4MU directly attenuated activation, proliferation, and differentiation of naive CD4+ T cells into Th1 cells. As 4MU has already been demonstrated to be safe for human use, we believe examining 4MU for the treatment of acute lung allograft rejection may be of clinical significance.

Only 20-40% of U.S. women conduct breast self-examination (BSE). This Southwest Oncology Group experimental study compared the impact of three interventions on BSE compliance.Subjects were randomly assigned to one of three arms: (1) physician message; (2) physician message and BSE class; or (3) physician message, BSE class, and reinforcement (phone and postcard). Compliance (frequency and accuracy) was measured by interview at intake and at 6 months and by phone contact at 1 year. Logistic and multiple regression were employed.This analysis included 2,233 subjects from six institutions. At 1 year the percentages of women doing BSE were 59, 62, and 78% for Arms 1-3, respectively; gains over intake frequency (27% average) were significant within each arm (P < or = 0.0001). At both 6 months and 1 year the differences between Arm 1 and Arm 2 average accuracy scores and the differences between Arm 2 and Arm 3 in the percentage of women doing BSE were significant (P < or = 0.0001). Findings within institutions were consistent with the overall findings.The addition of a BSE class increased accuracy over physician message alone; physician message, BSE class, and reinforcement gave the highest percentage of women doing BSE.

Abstract Endostatin is a naturally occurring collagen fragment with anti-angiogenic properties. We investigated the association between serum endostatin levels and DLCO in a cohort of patients with lymphangioleiomyomatosis (LAM). Associations of endostatin levels to clinical features of LAM were explored using logistic regression models. Endostatin levels were associated with DLCO and were higher in subjects with TSC-associated LAM compared to sporadic LAM. These data suggest that endostatin could be a predictive biomarker of decline in DLCO and that germline mutational inactivation of the TSC1 or TSC2 gene is associated with higher endostatin levels. These findings could offer novel insights into the pathogenesis of LAM.

I. A HISTORY A. RULE AGAINST PERPETUITIES This article begins with South Dakota's claim to fame, its 1983 Rule Against Perpetuities ("RAP") statute. This statute codified the 1979 case of [...], This article reviews the evolution of South Dakota&apos;s powerful trust, tax, and asset protection laws as well as the rationale behind these historic laws. The discussion will also highlight the support that both the trust industry and supporting legislation have received over the years from the current and former governors, (1) state legislatures, the South Dakota Division of Banking, (2) the South Dakota Division of Insurance, (3) as well as the South Dakota Trust Committee, (4) and most recently the South Dakota Trust Association (5)--all of which have played key roles in South Dakota&apos;s top rankings as a favorable trust situs.

Lymphatic vessels play an important role in health and in disease. In this study, we evaluated the effects of GSK3-β inhibition on lung lymphatic endothelial cells in vitro. Pharmacological inhibition and silencing of GSK3-β resulted in increased lymphangiogenesis of lung lymphatic endothelial cells. To investigate mechanisms of GSK3-β-mediated lymphangiogenesis, we interrogated the mammalian/mechanistic target of rapamycin pathway and found that inhibition of GSK3-β resulted in PTEN activation and subsequent decreased activation of AKT, leading to decreased p-P70S6kinase levels, indicating inhibition of the mTOR pathway. In addition, consistent with a negative role of GSK3-β in β-catenin stability through protein phosphorylation, we found that GSK3-β inhibition resulted in an increase in β-catenin levels. Simultaneous silencing of β-catenin and inhibition of GSK3-β demonstrated that β-catenin is required for GSK3-β-induced lymphangiogenesis.

A combination of multiaircraft and several satellite sensors were used to examine the core of Hurricane Erin on 10 September 2001, as part of the Fourth Convection and Moisture Experiment (CAMEX-4) program. During the first set of aircraft passes, around 1700 UTC, Erin was still at its maximum intensity with a central pressure of 969 hPa and wind speed of 105 kt (54 m [s.sup-1]). The storm was moving slowly northwestward at 4 m [s.sup.-1], over an increasingly colder sea surface. Three instrumented aircraft, the National Oceanic and Atmospheric Administration (NOAA) P3 with radar, the National Aeronautics and Space Administration (NASA) ER-2 at 19 kin, newly equipped with GPS dropwindsondes, and the NASA DC-8 with dropwindsondes flew in formation across the eye at about 1700 UTC and again 2.5 h later around 1930 UTC. The storm had weakened by 13 m [s.sup.-1] between the first and second eye penetrations. The warm core had a maximum temperature anomaly of only 11[degrees]C, located at 500 hPa, much weaker and lower than active hurricanes. The core appeared to slant rearward above 400 hPa. Even on the first penetration, airborne radar showed that the eyewall cloud towers were dying. The tops fell short of reaching 15 km and a melting band was found throughout. The tropopause had a bulge to 15.8-km elevation (environment -14.4 kin) above the dying convection. The paper presents a consistent picture of the vortex in shear interaction from a primarily thermodynamic perspective. A feature of Erin at this time was a pronounced wavenumber-1 convective asymmetry with all convective activity being confined to the forward quadrants on the left side of the shear vector as calculated from analyses. This is similar to that predicted by the mesoscale numerical models, which also predict that such small amounts of shear would not affect the storm intensity. In Erin, it is remarkable that relatively small shear produced such a pronounced asymmetry in the convection. From the three-dimensional analysis of dropsonde data, horizontal asymmetries in lower and middle tropospheric warming were identified. The warm anomalies are consistent with the pattern of mesoscale vertical motions inferred from the shear-induced wavenumber-1 asymmetry, dipole in rain intensity, and surface convergence.

The association between atopic dermatitis (AD) and conjunctivitis in adults has not been well established. We conducted a cross-sectional study of the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2002 to 2015 in order to evaluate the association between AD and conjunctivitis in U.S. adults. We performed multivariable logistic regression analyses adjusting for sociodemographic factors. An estimated total [95% CI] of 8,581,098 [7,592,037–9,570,160] weighted AD visits and 12,853,199,920 [12,808,269,186–12,898,131,033] weighted non-AD visits were utilized for our analyses. When compared to adults without AD, adults with AD had a fourfold higher risk of conjunctivitis (OR = 4.38; 95% CI, 1.39–13.79; p =.012) and specifically, an eight-fold higher risk of allergic conjunctivitis (OR = 8.03; 95% CI, 1.76–36.58; p =.007). Among adults with AD, 67.6% of their visits for conjunctivitis were for allergic conjunctivitis. Among adults without AD, 35.4% of their visits for conjunctivitis were for allergic conjunctivitis. Results of this study suggest that adults with AD have a significantly higher risk of conjunctivitis and specifically, allergic conjunctivitis when compared to those without AD. It is important for dermatology providers to be aware of this association and learn to recognize and potentially manage conjunctivitis in AD patients. [ABSTRACT FROM AUTHOR]